Edition 72 - February 2019 / Subject Review

Subject Review – Ed. 72

Marco A. Rivarola y Alicia Belgorosky. Servicio de Endocrinología, Hospital de Pediatría Garrahan, Buenos Aires, Argentina. 

For this issue of Endocrinología Pediátrica On Line, we have selected to comment on the following publication:

 

MINIREVIEW

J Clin Endocrinol Metab. 2019 Feb 1;104(2):341-348.  

Microvascular Endothelial Dysfunction in Human Obesity: Role of TNF-α. Virdis A1Colucci R2Bernardini N1Blandizzi C1Taddei S1Masi S1.

1 Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 2 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.

 

Abstract

CONTEXT: Endothelium guarantees vascular homeostasis by the opposite action of substances by vasodilating/antithrombogenic and vasoconstricting/ prothrombotic activities. Obesity is characterized by endothelial dysfunction associated with a condition of vascular low-grade inflammation. EVIDENCE ACQUISITION: Analysis of available basic or clinical papers published in peer-reviewed international journals on microcirculation and obesity. EVIDENCE SYNTHESIS: Vascular low-grade inflammation, which characterizes obesity, is secondary to abnormal production of proinflammatory cytokines, including TNF-α. TNF-α, generated either in small vessels or within the perivascular adipose tissue (PVAT) of patients with obesity, stimulates reactive oxygen species generation, mainly through NAD(P)H oxidase activation, which in turn reduces nitric oxide (NO) availability. These aspects are highlighted by the insulin resistance status and macronutrient intake that characterize the obesity condition. Oxidant excess has also been proposed as a mechanism whereby TNF-α interferes with the endothelin-1/NO system at the level of small vessels from patients with obesity.

CONCLUSIONS: In obesity, microvasculature from visceral fat is an important source of low-grade inflammation and oxidative stress that, together with the PVAT, directly contribute to vascular changes, favoring the development and acceleration of the vascular atherothrombotic process in this clinical condition.

Comments

Recently, a key role played by low-grade vascular inflammation on endothelial dysfunction and atherosclerosis emerged (Zhang H, 2008). In particular, TNF-α has been suggested as a key cytokine involved in reducing NO availability, an effect exerted by both inducing reactive oxygen species (ROS) generation and directly inhibiting eNO synthase (eNOS) activity (Libby P, 2009). Obesity is a complex chronic disease associated with increased CV morbidity and mortality (Klein S, 2004). The earliest manifestation of CV disease in obesity is endothelial dysfunction, an alteration that has been documented in several different vascular beds. A condition of chronic low grade inflammation secondary to the abnormal production of pro-inflammatory cytokines, including TNF-α (Dandona P, 1998), is considered the main mechanisms leading to endothelial dysfunction in obesity. There is a complex links among visceral adiposity, TNF-α, and microcirculation.

In conclusion, concordant findings emerging from several vascular beds and subsequent to different endothelial stimuli demonstrate that microvascular circulation represents a major target for obesity-related endothelial dysfunction. In isolated resistance vessels, in which the mechanisms accounting for endothelial dysfunction have been explored, a blunted activity of NO secondary to oxidant excess was demonstrated.

OBESITY AND ENDOTHELIAL DYSFUNTION.  A large body of literature

indicates that obesity is responsible for directly detrimental effects on the vasculature, independent from the concomitant presence of traditional cardiovascular risk factors commonly detected in obesity, including hypertension, diabetes mellitus, or dyslipidemia. These studies concordantly documented a dramatic reduction of endothelium-dependent relaxation of small resistance arteries from patients with obesity compared with lean controls. In conclusion, concordant findings emerging from several vascular beds and subsequent to different endothelial stimuli demonstrate that microvascular circulation represents a major target for obesity-related endothelial dysfunction. In isolated resistance vessels, in which the mechanisms accounting for endothelial dysfunction have been explored, a blunted activity of NO secondary to oxidant excess was demonstrated.

OBESITY AND INFLAMMATION: THE ROLE OF PERIVASCULAR ADIPOSE TISSUE (PVAT):

The generation of adipokines by fat cells can be regarded as an endocrine function and makes adipose tissue the largest endocrine organ of the body, particularly in patients affected by severe obesity. Major adipokines generated by fat cells include leptin, resistin, and adiponectin (Kershaw EE, 2004) Leptin is the main protein produced by adipocytes, and its blood concentration is proportional to the amount of adipose tissue. The ability of leptin to stimulate vasodilation by NO-independent or NO dependent mechanisms  however, requires, further investigation,

because available evidence is conflicting. Resistin, produced by adipogenesis, is involved in the development of insulin resistance and obesity (Steppan CM, 2001). Most of the convincing evidence on the effects of adipokines on the vascular wall involves the role of adiponectin. This adipokine, produced in mature adipocytes, has an opposite effect from leptin and resistin.  Adiponectin stimulates insulin sensitivity, reduces the expression of adhesion molecules on the endothelium, inhibits the transformation of macrophages into foam cells, and reduces the smooth muscle cells proliferation. Obesity is characterized by reduced production and activity of adiponectin, potentially reducing the protective effects of this adipokine against the development of endothelial dysfunction and the atherosclerotic process. A major mechanism whereby obesity can induce vascular changes involves the perivascular adipose tissue (PVAT), which exerts deleterious effects on the vasculature by secreting TNF- α and IL-6 (Yudkin JS, 2003). Experimental reports indicated TNF- α might stimulate ROS production via activation of NAD(P)H oxidase or by the activation of nuclear transcription factor-k B (NF-kB). This leads to mobilization and activation of macrophages, migration and proliferation of smooth muscle cells, and induction of adhesion molecule expression by the endothelial and smooth muscle cells of the vascular wall. An increased expression of TNF- α and the acquisition of a pro-oxidant phenotype by PVAT might represent common mechanisms leading to vascular changes in condition of insulin resistance. Indeed, PVAT from a rodent model of metabolic syndrome shows an increased TNF-α generation, together with a decreased adiponectin expression, a greater NADPH oxidase activity and a reduced expression of antioxidant •O22 dismutase (-1, -2, and -3). Results indicate that TNF-α inhibition may ameliorate vascular reactivity in patients with obesity during hyperinsulinemia, an effect consequent to a decreased oxidative stress (Greenstein AS, 2009). More recently, an interesting study conducted in isolated resistance vessels evidenced a specific role of PVAT-derived inflammation in the pathogenesis of vascular dysfunction. The evidence is in favor that in physiological conditions adipocytes contribute to the regulation of local vascular tone by modulating NO availability. Adipocyte hypertrophy, oxidant excess, and an increased accumulation of TNF-a in the PVAT of subjects with obesity result in a loss of this important regulation.

DOES VASCULATURE REPRESENT A MERE TARGET OF PVAT-DERIVED: TNF- α? Results produced in the authors’s laboratory demonstrate that small vessels from patients with obesity show a reduced NO availability secondary to excess ROS generation and that TNF-α promotes endothelial dysfunction by stimulating intravascular ROS generation. Comprehensively, these results suggest that NAD(P)H oxidase and iNOS are the two major enzymatic pathways mediating the increase of vascular wall oxidative stress induced by TNF-α in obesity.

ROLE OF INSULIN AND INSULIN RESISTANCE STATUS ON VASCULAR: INFLAMMATION. Insulin has vasodilatory effects on arteries, veins, and microcirculation. Such effects are mainly mediated by an increased stimulation and expression of eNOS within endothelial cells, which results in an increased NO Availability. Insulin might influence NO availability also by controlling systemic and local levels of inflammation and oxidative stress. The expression of the key pro-inflammatory transcription factor NF-kB is suppressed by insulin, particularly within the endothelial cell, and this leads to a reduced vascular inflammation. Therefore, conditions of insulin resistance (such as in human obesity) lead to ROS generation, vascular inflammation, and inhibition of eNOS expression.

LOCAL INFLAMMATION IN OBESITY: THE ROLE OF ENDOTHELIN-1 (ET-1): ET-1 participates to the vascular homeostasis by binding with two receptor subtypes, ETA and ETB. ETA receptors are represented on smooth muscle cells only, mediate contractions, and promote growth. In contrast, ETB receptors are located on smooth muscle cells (where they evoke contractions) and on endothelial cells (where they induce relaxation stimulating NO production) (Dhaun et al., 2008). In obesity a vascular ET-1/NO imbalance is commonly detected. Evidences suggest a potential role of the activated ET-1 system in the pathophysiology of complications of obesity-related hypertension.  Oxidative stress is one of the most important factors stimulating the increase of ET-1 synthesis in human coronary artery smooth muscle cells. Several studies provided evidence that, in small arteries from patients with obesity, the ET-1/NO imbalance is mediated by vascular and perivascular TNF-α excess, coupled with an increased vascular expression of ET-1 and ETA receptor.

CONCLUSION: In conclusion, obesity is characterized by a marked endothelial dysfunction caused by a reduced NO availability. In this clinical condition, PVAT plays a crucial role in generating pro-inflammatory cytokines, including TNF-α, with a documented direct deleterious effect toward the vasculature. In particular, although TNF-α promotes superoxide generation in the vascular wall via different pathways, the most important contribution might be due to the hyperactivation of NAD(P)H oxidase. In such a scenario, crucial roles are played by the insulin resistance status and chronic macronutrient intake, which contribute to obesity-associated chronic inflammatory status.


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